Association of MiR-146a Expression and Type 2 Diabetes Mellitus: A Meta-Analysis

Although deregulation of miR-146a has been reported in type 2 diabetes repeatedly, the direction of deregulation events (up or down) remained to be inconsistent in literatures. Therefore, in this study we performed a meta-analysis on the possible association between miR-146a expression levels and type 2 diabetes. A systematic literature searching of PubMed, ISI Web of Science and Google Scholar was performed up to the end of September 2016. Finally, a total of 12 studies including 344 diabetic patients and 316 controls were selected for meta-analysis. All statistical analysis was performed using the metafor package with R software. Moreover, publication bias was assessed by Egger’s and sensitivity analysis was applied on the meta-analysis. The results are presented as log10 odds ratios (logORs), 95% confidence intervals (CI) with relevant P values. The results revealed that miR-146a was downregulated in type 2 diabetes cases compared with normal subjects (P=0.01, logOR:-4.76, 95% CI:-8.41, -1.11). Furthermore, sub-group analysis showed that the association between miR-146a expression levels and type 2 diabetes in whole blood (P<0.001) and PBMCs (P<0.001) samples were significant. However, this association was not significant in the serum (P=0.67) and plasma (P=0.90) samples. Our finding suggests that miR-146a downregulation could be associated with type 2 diabetes susceptibility. Further investigations with larger sample size are required to evaluate this association in the type 2 diabetes pathogenesis.

Since the discovery in 1993, there has been a steady increase in the number of studies investigating the role of circulatory microRNAs (miRNAs) as highly stable and non-invasive biomarkers (6,7). MiRNAs are short 20-23 nucleotides non-coding RNAs molecules that modulate gene expression at post-transcriptional level by binding to 3' UTR target sites of mRNAs (8). They have essential roles in homeostasis of glucose and lipid metabolism, development of pancreatic β cells, production and secretion of insulin (9,11 English. To find eligible articles, a combination of the following key words was used: "miR-146a", "expression", "profiling", "type 2 diabetes", "circulating", "plasma", "serum", and "blood". In additon, to identify additional eligible studies, we scanned the reference lists of reviews and publications selected for inclusion in this paper.

Data extraction and quality assessment
The required data were retrieved by two

Statistical analysis
All analyses were performed using the metafor package with R statistical software 3.1. Metaanalysis was performed as described elsewhere (24). To assess the statistical significance, we made 2x2 contingency

The characteristics of included studies
After titles and abstracts initial screening, 10 Finally, a total of 12 studies/sub-studies including 344 T2D patients and 316 normal samples were selected for meta-analysis (Table 1).

Meta-analysis of miR-146a expression in T2D
We applied a random-effects model for the meta-analysis, since I 2 (total heterogeneity/ total variability) was as 90.15%. Overall, meta-analysis revealed that miR-14a was downregulated in T2D        Studies have shown that miR-146a interacts directly with interleukin-1 receptor-associated kinase 1 (IRAK1)/TNF receptor-associated factor 6 (TRAF6), thus attenuating the inflammatory cytokines production in macrophages (26,27). It has been reported that patients suffering from T2D have significantly decreased levels of miR-146a (15,21).
yet, in contrast to these findings, an increased expression of this miRNA has also been previously reported (5,14).
Further, the subgroup analysis by sample type showed that the association between miR-146a expression level and T2D was significant in PBMCs and whole blood samples, whereas it was not significant for serum and plasma samples. As a result, determination of miR-146a expression level as molecular marker for T2D can be more useful in PBMCs than in serum and plasma. One possible reason for this finding may be due to the fact that miRNAs expressions are cell and tissue specific (28). It has been shown that miR-146a levels are much more abundant in the PBMCs including lymphocytes and macrophages/monocytes (29).
Importantly, there is a report which performed a meta-analysis on miR-146a expression in different tissues in human and model organisms (24). Although we used similar methodology to Considering such criteria makes our study more accurate in determining the potential role of miR-146a as non-invasive biomarker for T2D and its complications.
Even though we tried to perform a well- In conclusion, our finding suggest that miR-146a downregulation could be associated with T2D susceptibility. Furthermore, this result suggests that miR-146a can be considered as a potent marker to predict the clinical outcome of diabetes. This association needs to be confirmed through more clinical investigations with larger sample size and well characterized study populations.